EP3119779A1 - Azaindole acetic acid derivatives and their use as prostaglandin d2 receptor modulators - Google Patents

Azaindole acetic acid derivatives and their use as prostaglandin d2 receptor modulators

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Publication number
EP3119779A1
EP3119779A1 EP15714030.2A EP15714030A EP3119779A1 EP 3119779 A1 EP3119779 A1 EP 3119779A1 EP 15714030 A EP15714030 A EP 15714030A EP 3119779 A1 EP3119779 A1 EP 3119779A1
Authority
EP
European Patent Office
Prior art keywords
methyl
tetrahydro
indol
pyrido
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP15714030.2A
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German (de)
French (fr)
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EP3119779B1 (en
Inventor
Hamed Aissaoui
Christoph Boss
Patrick BOUIS
Julien Hazemann
Romain Siegrist
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Idorsia Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Priority to HRP20181555TT priority Critical patent/HRP20181555T1/en
Priority to RS20181191A priority patent/RS57867B1/en
Priority to MA39750A priority patent/MA39750B1/en
Priority to PL15714030T priority patent/PL3119779T3/en
Priority to SI201530381T priority patent/SI3119779T1/en
Publication of EP3119779A1 publication Critical patent/EP3119779A1/en
Application granted granted Critical
Publication of EP3119779B1 publication Critical patent/EP3119779B1/en
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to azaindole acetic acid derivatives of formula (I) and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2 receptor (“DP receptor”) modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.
  • prostaglandin receptor modulators most particularly as prostaglandin D 2 receptor (“DP receptor") modulators
  • such derivatives may be used alone or in pharmaceutical compositions for the treatment of both, chronic and acute allergic/immune diseases/disorders such as asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ- specific subsets of the latter), hypereosinophilic syndromes like eosinophilic
  • mast cells are activated and release mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D 2 (PGD 2 ).
  • TxA2 thromboxane A2
  • CysLTs cysteinyl leukotrienes
  • PPD 2 prostaglandin D 2
  • mediators interact with their respective receptors and cause physiological effects such as increased vascular permeability, edema, pruritus, nasal and pulmonary congestion, bronchoconstriction, and mucus secretion.
  • An increased vascular permeability for example, allows excessive infiltration of eosinophilic and basophilic leukocytes into the tissue and thus amplifies the allergic response.
  • PGD 2 is an agonist known to act on two G-protein-coupled receptors, the PGD 2 receptor DP1 and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as "DP2 receptor")-
  • Elevated PGD 2 levels are considered to cause inflammation as observed in allergic diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic dermatitis and the like. Therefore, blocking the interaction of PGD 2 with its receptors is considered a useful therapeutic strategy for the treatment of such diseases.
  • GB 2388540 discloses the use of ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)- 1 ,2,3,4-tetrahydrocarbazole-9-propionic acid), a TxA2 receptor (also referred to as "TP receptor") antagonist with additional antagonistic activity on CRTH2, for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjunctivitis.
  • TP receptor also referred to as "TP receptor”
  • WO 201 1/1 17798 and WO 2012/140612 disclose (3-heteroarylamino-1 ,2,3,4-tetrahydro- 9H-carbazol-9-yl)-acetic acid and (7-heteroarylamino-6,7,8,9-tetrahydropyrido[1 ,2-a]indol- 10-yl)acetic acid derivatives, respectively, which derivatives have CRTH2 antagonistic activity.
  • the present invention relates to azaindole acetic acid derivatives of formula (I),
  • R 1 represents hydrogen, (C 1 _ 4 )alkyl, (C ⁇ fluoroalkyl, (Ci -4 )alkoxy, or halogen;
  • R 2 represents hydrogen or methyl
  • the compounds of formula (I) as defined in any one of embodiments 1) to 19), may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of formula (I) may thus be present as mixtures of stereoisomers or in stereoisomerically enriched form, preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • enriched for example when used in the context of enantiomers, is understood in the context of the present invention to mean especially that the respective enantiomer is present in a ratio (mutatis mutandis: purity) of at least 70:30, and notably of at least 90:10 (mutatis mutandis: purity of 70% / 90%) with respect to the respective other enantiomer.
  • the term refers to the respective essentially pure enantiomer.
  • essentially for example when used in a term such as "essentially pure” is understood in the context of the present invention to mean especially that the respective stereoisomer / composition / compound etc.
  • alkyl used alone or in combination, refers to a straight or branched chain alkyl group containing one to four carbon atoms.
  • (C x . y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C 1-4 )alkyl group contains from one to four carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and fe/f-butyl; preferred is methyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • (C x . y ) alkoxy refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (C ⁇ alkoxy group contains from one to four carbon atoms.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, / ' so-propoxy, n-butoxy, / ' so-butoxy, sec-butoxy and tert- butoxy; preferred is methoxy.
  • (C )fluoroalkyl refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • a (C ⁇ fluoroalkyl group contains one or two carbon atoms in which one to five hydrogen atoms have been replaced with fluorine.
  • Representative examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl; preferred is trifluoromethyl.
  • halogen means fluoro, chloro, bromo or iodo; preferred is fluoro.
  • a further embodiment of the invention relates to compounds of formula (I) according to embodiment 1), wherein
  • R 1 represents hydrogen, methyl, trifluoromethyl, methoxy, or fluoro
  • a further embodiment of the invention relates to compounds of formula (I) according to embodiment 1), wherein
  • R 1 represents hydrogen, (C 1-4 )alkyl, or (C ⁇ alkoxy;
  • a further embodiment of the invention relates to compounds of formula (I) according to embodiment 1), wherein
  • R 1 represents hydrogen, methyl, or methoxy
  • a further embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 4), wherein
  • R 2 represents methyl; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
  • a further embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 4), wherein
  • R 2 represents hydrogen
  • a further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), wherein the absolute configuration of the stereogenic center is as depicted in formula (l st i)
  • a further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), wherein the absolute configuration of the stereogenic center is as depicted in formula (l st 2)
  • a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1) or 5) to 8), wherein
  • R 1 represents fluoro
  • Examples of compounds of formula (I) as defined in embodiment 1) are selected from the group consisting of: 2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro
  • a stereogenic center which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration; for example a compound listed as 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy- 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid may be (f?)-2-(8-((5- chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid , (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6, 7,8,9- tetrahydro-5H-pyrido[3,2-b]indol
  • Preferred examples of compounds of formula (I) as defined in embodiment 1 ) are selected from the group consisting of:
  • the compound of formula (I) as defined in embodiment 1 ) is: 2-(8-((5-chloropyrimidin-2-yl)ami ⁇
  • the compound of formula (I) as defined in embodiment 1) is: 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid (and notably (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid);
  • the compound of formula (I) as defined in embodiment 1) is:
  • asthma selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific
  • any reference to a compound of formula (I) as defined in any one of embodiments 1) to 19) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • the present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • the term “about” (or alternatively “around”) placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” (or alternatively “around”) placed before a temperature ⁇ " refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.
  • room temperature refers to a temperature of about 25°C.
  • the compounds of formula (I) as defined in any one of embodiments 1) to 19) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) as defined in any one of embodiments 1 ) to 19).
  • the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
  • Another aspect of the invention concerns a method for the prevention or the treatment of a disease or disorder as mentioned below in a patient comprising the administration to said patient of a pharmaceutically active amount of a compound of formula (I) as defined in any one of embodiments 1 ) to 19) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatos
  • the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of nasal polyposis, Still's disease (systemic onset juvenile idyiopathic arthritis) and cystic fibrosis.
  • the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of asthma, allergic asthma, eosinophilic asthma, severe asthma, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria and eczema.
  • diseases selected from the group consisting of asthma, allergic asthma, eosinophilic asthma, severe asthma, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria and e
  • the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymph
  • the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
  • the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of asthma, eosinophilic asthma, allergic rhinitis, atopic dermatitis, nasal polyposis, food allergy (notably IgE-mediated food allergy), urticaria (notably chronic urticaria), eosinophilic esophagitis, Churg Strauss Syndrome, hypereosinophilic syndrome, eosinophilic pneumonia (notably chronic eosinophilic pneumonia), DRESS syndrome, Still's disease, COPD and cystic fibrosis (and especially asthma, eosinophilic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy, chronic urticaria, eosinophilic esophagitis and Churg Strauss Syndrome).
  • diseases selected from the group
  • the invention also relates to the use of a compound of formula (I) according to any one of embodiments 1) to 19) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.
  • the present invention also relates to pharmaceutically acceptable salts and to pharmaceutical compositions and formulations of compounds of formula (I) according to any one of embodiments 1) to 19).
  • a pharmaceutical composition according to the present invention contains at least one compound of formula (I) according to any one of embodiments 1) to 19) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.
  • any reference to a compound of formula (I), (l ST i) or (l S T2> in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
  • the preferences indicated for the compounds of formula (I) of course apply mutatis mutandis to the compounds of formula (l ST i) and to the compounds of formula (l ST 2) as well as to the salts and pharmaceutically acceptable salts of the compounds of formula (I), of formula (l ST i) or of formula (l S T2) -
  • compounds of formula (I) modulate as antagonists the PGD 2 activation of the CRTH2 receptor.
  • the biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays.
  • the ability of the compounds of formula (I) to bind to the CRTH2 receptor may be measured by methods similar to those described in the literature (Arimura A. et al. , J. Pharmacol. Exp. Ther. 2001 , 298(2), 41 1 -419; and Sawyer N. et al., Br. J. Pharmacol, 2002, 137, 1 163-1 172, respectively) and by the assays described below in the experimental part.
  • a further aspect of the invention is a process for the preparation of compounds of formula (I).
  • Compounds according to formula (I) of the present invention can be prepared according to the sequence of reactions outlined in the schemes below wherein R 1 and R 2 are as defined for formula (I). Other abbreviations used are defined in the experimental section.
  • the compounds of formula (I) may be prepared from the respective azaindole derivative (4) which itself may be synthesized by MW irradiation of the respective 3-amino-2-bromo- pyridine or 3-amino-2-chloro-pyridine derivative (1) with a 4-(5-chloro-pyrimidin-2-yl)amino- cyclohexanone derivative (3) in the presence of a catalyst such as Pd(Ph 3 P) 4 in pyridine or by reaction of the respective Boc protected hydrazine derivative (6) with a 4-(5-chloro- pyrimidin-2-yl)amino-cyclohexanone derivative (3) in the presence of an acid such as sulfuric acid.
  • the Boc protected hydrazine derivative (6) may be prepared by reaction of the respective bromo-pyridine derivative (5) with di-tert-butyl-aza-dicarboxylate in the presence of a base such as butyllithium in an aprotic solvent such as THF.
  • the 4-(5-chloro-pyrimidin-2-yl)amino-cyclohexanone derivative (3) may be prepared by a reductive amination of commercially available 1 ,4-dioxaspiro[4,5]decan-8-one (2) with the desired amine R 2 -NH 2 in the presence of a reducing agent such as NaBH(OAc) 3 in an aprotic solvent such as DCM, followed by reaction with 2,5-dichloropyrimidine (R 3 -CI) in the presence of a base such as DIEA in an aprotic solvent such as DMF, and acetal deprotection under acidic condition such as HCI in methanol.
  • a reducing agent such as NaBH(OAc) 3
  • aprotic solvent such as DCM
  • compounds of formula (I) wherein R 2 represents hydrogen may be prepared from the respective azaindole derivative (9) which itself may be synthesized by MW irradiation of the respective 3-amino-2-bromo-pyridine (7) with commercially available tert- butyl (4-oxocyclohexyl)carbamate (8) in the presence of a catalyst such as Pd(Ph 3 P) 4 in pyridine.
  • Compounds of formula (I) wherein R 2 represents hydrogen may also be prepared from the respective azaindole derivative (13) which itself may be synthesized by reaction of the respective commercially available pyridine hydrazine hydrochloride derivative (11) with commercially available benzyl (4-oxocyclohexyl)carbamate (12) in the presence of an acid such as sulfuric acid. Alkylation of the azaindole derivative (13) with ethyl bromoacetate in the presence of a base such as NaH in an aprotic solvent such as DMF followed by Cbz deprotection with an acid such as HBr in acetic acid gives the desired azaindole acetic acid ethylester (14).
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as TEA and/or DEA) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • EtOH eluent A
  • eluent B hexane
  • HPLC/MS analyses are performed on a Agilent 1 100 system, equipped with a Dionex P580 binary pump, a Dionex PDA-100 Photodiode Array Detector and a Finnigan AQA mass spectrometer.
  • Preparative HPLC/MS purifications are performed on a Gilson 333/334 binary high pressure gradient pump system with a Gilson 215 autosampler and fraction collector, a Dionex UVD340U DAD detector, a polymerlabs PL-ELS 1000 ELS detector and a Thermo MSQ Plus MS detector, using a Waters Atlantis T3 column (10 ⁇ , 30 ⁇ 75 mm), with a linear gradient of water/ 0.5% formic acid (B) and MeCN (A) starting from 80/20 to 5/95 (B)/(A) over 5 min.; flow rate 75 ml/min.
  • Preparative HPLC/MS purifications are performed on a Gilson 333/334 binary high pressure gradient pump system with a Gilson 215 autosampler and fraction collector, a Dionex UVD340U DAD detector, a polymerlabs PL-ELS 1000 ELS detector and a Thermo MSQ Plus MS detector, using a Waters XBridge C18 column (10 ⁇ , 30 ⁇ 75 mm), with a linear gradient of water/ 0.5% 25% NH 4 OH (B) and MeCN (A) starting from 80/20 to 5/95 (B)/(A) over 5 min.; flow rate 75 ml/min.
  • Typical conditions of chiral HPLC are an isocratic mixture of 30% heptane + 0.05% DEA and 70% EtOH + 0.05% DEA, at a flow rate of 0.8 mL/min., detection at 210 nm (chiral HPLC-1 ) or an isocratic mixture of 40% heptane and 60% EtOH + 0.1 % TFA, at a flow rate of 1 .0 mL/min., detection at 210 nm (chiral HPLC-2) or an isocratic mixture of 50% heptane + 0.05% DEA and 50% EtOH + 0.05% DEA, at a flow rate of 0.8 mL/min., detection at 210 nm (chiral HPLC-3), or an isocratic mixture of 20% heptane and 80% EtOH + 0.1 % TFA, at a flow rate of 0.8 mL/min., detection at 210 nm (chiral HPLC-4).
  • Preparative HPLC over a chiral stationary phase are performed on a Daicel ChiralPak AD- H (20 X 250 mm, 5 ⁇ ) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of 50% EtOH and 50% heptane, at a flow rate of 16 mL/min., detection at 210 nm (chiral HPLC-5) or an isocratic mixture of 50% EtOH + 0.05% DEA and 50% heptane, at a flow rate of 34 mL/min, detection at 210 nm (chiral HPLC-6) or an isocratic mixture of 50% EtOH + 0.1 % DEA and 50% heptane, at a flow rate of 16 mL/min, detection at 210 nm (chiral HPLC-7).
  • the reaction mixture was dissolved in EA, and washed with a saturated solution of NaHC0 3 .
  • the organic extract was dried over MgS0 4 , filtered and concentrated in vacuo.
  • the residue was purified by FC (n- heptane to n-heptane/EA: 7/3) to give the desired product as a racemate.
  • the membrane fragments were then centrifuged at 3000 g for 20 minutes and resuspended in buffer C (Buffer C: 75 mM Tris , 25 mM MgCI 2 , 250 mM Saccharose pH 7.4). Aliquots of membrane fragements were stored at -20°C.
  • Binding assay was performed in a final assay volume of 250 ⁇ . First, 25 ⁇ of test compound, previously diluted in Binding-Buffer (Binding-Buffer: 50 mM Tris-Base, 100 mM NaCI, 1 mM EDTA, 0.1 % BSA (protease free), 0.01 % NaN 3 , 10mM MnCI 2 pH 7.0) was placed into each well. After addition of 75 ⁇ Binding-Buffer, 50 ⁇ of the radioligand 3 H- PGD 2 (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well.
  • Binding-Buffer 50 mM Tris-Base, 100 mM NaCI, 1 mM EDTA, 0.1 % BSA (protease free), 0.01 % NaN 3 , 10mM MnCI 2 pH 7.0
  • Binding assay was started by addition of 100 ⁇ CRTH 2 membrane fragments, reaching a final concentration of 20 ⁇ g/well. For non-specific binding, PGD 2 was added to the reaction mixture to 10 mM final concentration. This assay mix was incubated for 90 minutes at room temperature and then filtered through a GF/C filter 96-well plate which was pre- soaked for 3 hours in 0.5% polyethyleneimine (PEI). The filter-wells were washed three times with ice cold Binding-Buffer. Then, 40 ⁇ of Microscint-40 (Packard) was added to each well and the retained radioactivity quantified in a Topcount (Packard). Antagonistic activities of exemplified compounds are displayed in Table 4.
  • Binding-Buffer-HSA Binding- buffer + 0.5% Sigma Albumin from Human serum A1887 (instead of 0.1 % BSA).
  • a volume of 25 ⁇ test compound, previously diluted in Binding-Buffer-HSA was placed into each well.
  • 75 ⁇ Binding-Buffer-HSA 50 ⁇ of 3 H-PGD 2 (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well. Remaining protocol was identical as described above.
  • Antagonistic activities of exemplified compounds are displayed in Table 5.
  • Test compounds at various concentrations, were preincubated 10min in human plasma (anticoagulated with a thrombin inhibitor). Then, human plasma was added to the polymorphonuclear cells to 50% of final assay volume with polymorphonuclear cells at 4x10 6 cells/ml.
  • the polymorphonuclear cells were activated for 5 min at 37°C by addition of PGD 2 at 100 nM final concentration. Activation was stopped by addition of 0.5 ml paraformaldehyde (1 %).
  • Intracellular calcium mobilization assay FLIPR: Intracellular calcium mobilization assay
  • HEK-293 stably expressing the hCRTH2 receptor under the control of the cytomegalovirus promotor from a single insertion of the expression vector pcDNA5 (Invitrogen), are grown to confluency in DMEM (low glucose, Gibco) medium supplemented with 10% fetal calf serum (Bioconcept, Switzerland) under standard mammalian cell culture conditions (37°C in a humidified atmosphere of 5% C0 2 ).
  • DMEM low glucose, Gibco
  • fetal calf serum Bioconcept, Switzerland
  • Cells are detached from culture dishes using a dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, and collected by centrifugation at 200 g at rt for 5 min in assay buffer (equal parts of Hank's BSS (HBSS, Bioconcept) and DMEM (low glucose, without phenol red, Gibco)).
  • dissociation buffer 0.02% EDTA in PBS, Gibco
  • assay buffer equal parts of Hank's BSS (HBSS, Bioconcept) and DMEM (low glucose, without phenol red, Gibco)
  • test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in assay buffer to concentrations required for inhibition dose response curves.
  • Prostaglandin D 2 Biomol, Plymouth Meeting, PA is used as an agonist.
  • Emission peak values above base level after prostaglandin D 2 addition are exported after base line subtraction. Values are normalized to high-level control (no test compound added) after subtraction of base line value (no prostaglandin D 2 added).
  • the program XLIfit 3.0 (IDBS) is used to fit the data to a single site dose response curve of the equation (A+((B-A)/(1 +((C/x) A D))))) and to calculate the IC 50 values.
  • hepatocytes were isolated according to a standard procedure, i.e. by in situ perfusion of the liver with a collagenase solution. The viability of the purified hepatocytes, checked by the trypan blue dye exclusion method was greater than 85%.
  • the isolated hepatocytes were resuspended in standard Williams Medium E, without phenol red, supplemented (WME supp.) with transferrin (100 ⁇ g/ml), triiodothyronine (10 ⁇ g/ml), gentamicin (50 ⁇ g/ml), hydrocortison hemisuccinate (13.36 ⁇ g/ml), glucagon (5 ⁇ g/ml), HEPES (10 mM), inosin (10 ⁇ g/ml), insulin (10 ⁇ g/ml), streptomycin (100 ⁇ g/ml) and penicillin (100 U/ml) and 10% fetal bovine serum (FBS).
  • transferrin 100 ⁇ g/ml
  • triiodothyronine 10 ⁇ g/ml
  • gentamicin 50 ⁇ g/ml
  • hydrocortison hemisuccinate 13.36 ⁇ g/ml
  • glucagon 5 ⁇ g/
  • the cells were plated in collagen-coated 24-well plates at an initial density of 2x10 5 cells/well. After 4 h for attachment to the culture-plates, the medium was aspirated and replaced by fresh WME supp. without FBS containing the test compounds and incubated for 24 h at 37°C in a 95% 0 2 and 5% C0 2 atmosphere. For each experiment, i.e., with each batch of hepatocytes, treatments with the test compounds were done in quadriplicate. Quadriplicate controls (treatment with the vehicle only) were also present on each culture plate.
  • test compounds were prepared in DMSO a few hours before treatment start. Appropriate dilutions of these stock solutions were added to the culture media just prior to the treatment in order to give final concentrations of 0, 3, 10, 30, 100 and 300 ⁇ . The final concentration of the vehicle DMSO was 1 % (v/v).
  • the morphology of the hepatocyte monolayers was monitored by light microscopy after 24 hours of exposure to the test compounds. Treatment related effects are described according to the following grading:
  • LDH lactate dehydrogenase
  • LCC cytotoxic concentration
  • NoEC no effect concentration
  • Liver toxicity of a compound of formula (I) can be analyzed by oral treatment in rats and a non-rodent species of up to 4 weeks using three different doses of the compound. Reversibility of possible toxicity can be investigated in a subsequent treatment free period (recovery period). Dose levels are chosen based on dose range finding studies in the respective species. The high dose is expected to identify organ toxicity close at the maximum tolerated dose. The mid and low dose is chosen based on estimated therapeutic human exposures. Exposure of the compound is measured at each dose level.
  • liver biomarkers such as for example liver enzymes, protein, triglycerides or cholesterol
  • liver biomarkers such as for example liver enzymes, protein, triglycerides or cholesterol
  • Hematoxi!in-Eosin stained liver slices is examined microscopically to directly assess possible organ damage. Specialized stainings of liver slices might be required to further characterize possible liver findings.

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Abstract

The present invention relates to azaindole acetic acid derivatives of formula (I), wherein R1 and R2 are as described in the description, and their use as prostaglandin receptor modulators, most particularly as prostaglandin D2 receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

Description

Azaindole acetic acid derivatives
and their use as prostaglandin D2 receptor modulators
Field of the invention:
The present invention relates to azaindole acetic acid derivatives of formula (I) and their use as prostaglandin receptor modulators, most particularly as prostaglandin D2 receptor ("DP receptor") modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation. In particular, such derivatives may be used alone or in pharmaceutical compositions for the treatment of both, chronic and acute allergic/immune diseases/disorders such as asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ- specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
Background of the invention:
As a response to allergen exposure in allergic conditions, mast cells are activated and release mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2). These mediators interact with their respective receptors and cause physiological effects such as increased vascular permeability, edema, pruritus, nasal and pulmonary congestion, bronchoconstriction, and mucus secretion. An increased vascular permeability for example, allows excessive infiltration of eosinophilic and basophilic leukocytes into the tissue and thus amplifies the allergic response.
Current treatments of allergic diseases comprise agents that can block or otherwise interrupt such interactions, e.g. anti-histamines (histamine H1 receptor antagonists), leukotriene receptor antagonists, beta-adrenergic receptor agonists, and corticosteroids. Generally, treatments with anti-histamines and leukotriene antagonists are limited in efficacy, and long-term usage of corticosteroids is often associated with unwanted side effects. PGD2 is an agonist known to act on two G-protein-coupled receptors, the PGD2 receptor DP1 and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as "DP2 receptor")-
Elevated PGD2 levels are considered to cause inflammation as observed in allergic diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic dermatitis and the like. Therefore, blocking the interaction of PGD2 with its receptors is considered a useful therapeutic strategy for the treatment of such diseases.
GB 2388540 discloses the use of ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)- 1 ,2,3,4-tetrahydrocarbazole-9-propionic acid), a TxA2 receptor (also referred to as "TP receptor") antagonist with additional antagonistic activity on CRTH2, for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjunctivitis. In T. Ishizuka et al., Cardiovascular Drug Rev. 2004, 22(2), 71 -90 effects of ramatroban on late-phase inflammation are described. Furthermore, oral bioavailability of ramatroban and its ability to inhibit prostaglandin D2-induced eosinophil migration in vitro has been reported (Journal of Pharmacology and Experimental Therapeutics, 305(1 ), p.347-352 (2003)). Azaindole acetic acid derivatives with CRTH2 antagonistic activity have been disclosed in WO 2010/0541 13, WO 2010/0541 14 and B.A. Stearns et al., Bioorg. Med. Chem. Lett. 2009, 19, 4647-4651 .
WO 201 1/1 17798 and WO 2012/140612 disclose (3-heteroarylamino-1 ,2,3,4-tetrahydro- 9H-carbazol-9-yl)-acetic acid and (7-heteroarylamino-6,7,8,9-tetrahydropyrido[1 ,2-a]indol- 10-yl)acetic acid derivatives, respectively, which derivatives have CRTH2 antagonistic activity.
It has now surprisingly been found that particular azaindole acetic acid derivatives substituted with a 5-chloro-pyrimidin-2-ylamino-group have significantly improved properties in an in-vitro cytotoxicity assay in primary cultured rat hepatocytes. It is thus expected that the present compounds have an improved toxicity profile in-vivo. Description of the invention:
1) The present invention relates to azaindole acetic acid derivatives of formula (I),
(I)
wherein
R1 represents hydrogen, (C1_4)alkyl, (C^^fluoroalkyl, (Ci-4)alkoxy, or halogen; and
R2 represents hydrogen or methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
Definitions provided herein are intended to apply uniformly to the compounds of formula (I) as defined in any one of embodiments 1) to 19), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
The compounds of formula (I) as defined in any one of embodiments 1) to 19), may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of formula (I) may thus be present as mixtures of stereoisomers or in stereoisomerically enriched form, preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
The term "enriched", for example when used in the context of enantiomers, is understood in the context of the present invention to mean especially that the respective enantiomer is present in a ratio (mutatis mutandis: purity) of at least 70:30, and notably of at least 90:10 (mutatis mutandis: purity of 70% / 90%) with respect to the respective other enantiomer. Preferably the term refers to the respective essentially pure enantiomer. The term "essentially", for example when used in a term such as "essentially pure" is understood in the context of the present invention to mean especially that the respective stereoisomer / composition / compound etc. consists in an amount of at least 90, especially of at least 95, and notably of at least 99 per cent by weight of the respective pure stereoisomer / composition / compound etc.. The term "alkyl", used alone or in combination, refers to a straight or branched chain alkyl group containing one to four carbon atoms. The term "(Cx.y)alkyl" (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C1-4)alkyl group contains from one to four carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, /'so-propyl, n-butyl, /'so-butyl, sec-butyl and fe/f-butyl; preferred is methyl.
The term "alkoxy", used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term "(Cx.y) alkoxy" (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C^alkoxy group contains from one to four carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, /'so-propoxy, n-butoxy, /'so-butoxy, sec-butoxy and tert- butoxy; preferred is methoxy.
The term "(C )fluoroalkyl" (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. For example a (C^fluoroalkyl group contains one or two carbon atoms in which one to five hydrogen atoms have been replaced with fluorine. Representative examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl; preferred is trifluoromethyl.
The term halogen means fluoro, chloro, bromo or iodo; preferred is fluoro.
2) A further embodiment of the invention relates to compounds of formula (I) according to embodiment 1), wherein
R1 represents hydrogen, methyl, trifluoromethyl, methoxy, or fluoro;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
3) A further embodiment of the invention relates to compounds of formula (I) according to embodiment 1), wherein
R1 represents hydrogen, (C1-4)alkyl, or (C^alkoxy;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
4) A further embodiment of the invention relates to compounds of formula (I) according to embodiment 1), wherein
R1 represents hydrogen, methyl, or methoxy;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
5) A further embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 4), wherein
R2 represents methyl; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
6) A further embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 4), wherein
R2 represents hydrogen;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
7) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), wherein the absolute configuration of the stereogenic center is as depicted in formula (lsti)
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
8) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 6), wherein the absolute configuration of the stereogenic center is as depicted in formula (lst2)
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
9) A further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments 1) or 5) to 8), wherein
R1 represents fluoro;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
10) Examples of compounds of formula (I) as defined in embodiment 1) are selected from the group consisting of: 2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro
acid;
2-(8-((5-chloropyrimidin-2-yl)(methy ^
yl)acetic acid ;
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6 ,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6 ,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6 ,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid; and
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-6 ,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetic acid;
or salts (in particular pharmaceutically acceptable salts) of such compounds;
it is to be understood for any of the above listed compounds, that a stereogenic center, which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration; for example a compound listed as 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy- 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid may be (f?)-2-(8-((5- chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid , (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6, 7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid or any mixture thereof.
1 1 ) Preferred examples of compounds of formula (I) as defined in embodiment 1 ) are selected from the group consisting of:
(S)-2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid ;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetic acid; and
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetic acid;
or salts (in particular pharmaceutically acceptable salts) of such compounds;
12) In a preferred embodiment the compound of formula (I) as defined in embodiment 1 ) is: 2-(8-((5-chloropyrimidin-2-yl)ami^
acid (and notably (S)-2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid);
or a salt (in particular a pharmaceutically acceptable salt) of the compound;
13) In a preferred embodiment the compound of formula (I) as defined in embodiment 1) is: 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid (and notably (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid);
or a salt (in particular a pharmaceutically acceptable salt) of the compound;
14) In another preferred embodiment the compound of formula (I) as defined in embodiment 1) is:
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid (and notably (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2- methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid);
or a salt (in particular a pharmaceutically acceptable salt) of the compound;
15) In another preferred embodiment the compound of formula (I) as defined in embodiment 1) is:
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid (and notably (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2- fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid);
or a salt (in particular a pharmaceutically acceptable salt) of the compound;
16) In another preferred embodiment the compound of formula (I) as defined in embodiment 1) is:
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid (and notably (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2- methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid);
or a salt (in particular a pharmaceutically acceptable salt) of the compound;
17) In another preferred embodiment the compound of formula (I) as defined in embodiment 1) is:
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetic acid (and notably (S)-2-(8-((5-chloropyrimidin-2- yl)(methyl)amino)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid);
or a salt (in particular a pharmaceutically acceptable salt) of the compound; 18) In another preferred embodiment the compound of formula (I) as defined in embodiment 1) is:
2-(8-((5-chloropyrimidin-2-yl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid (and notably (S)-2-(8-((5-chloropyrimidin-2-yl)amino)-2-fluoro-6, 7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid);
or a salt (in particular a pharmaceutically acceptable salt) of the compound;
19) The invention, thus, relates to compounds of the formula (I) as defined in embodiment
1) , and to such compounds further limited by the characteristics of any one of embodiments
2) to 18), all under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis. Especially the following embodiments relating to the compounds of formula (I) are thus possible and intended and herewith specifically disclosed in individualized form: 1 , 2+1 , 3+1 , 4+1 , 5+1 , 5+2+1 , 5+3+1 , 5+4+1 , 6+1 , 6+2+1 , 6+3+1 , 6+4+1 , 7+1 , 7+2+1 , 7+3+1 , 7+4+1 , 7+5+1 , 7+5+2+1 , 7+5+3+1 , 7+5+4+1 , 7+6+1 , 7+6+2+1 , 7+6+3+1 , 7+6+4+1 , 8+1 , 8+2+1 , 8+3+1 , 8+4+1 , 8+5+1 , 8+5+2+1 , 8+5+3+1 , 8+5+4+1 , 8+6+1 , 8+6+2+1 , 8+6+3+1 , 8+6+4+1 , 9+1 , 9+5+1 , 9+6+1 , 9+7+1 , 9+7+5+1 , 9+7+6+1 , 9+8+1 , 9+8+5+1 , 9+8+6+1 , 10+1 , 1 1 +1 , 12+1 , 13+1 , 14+1 , 15+1 , 16+1 , 17+1 , and 18+1 ; in the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, "5+2+1 " for example refers to embodiment 5) depending on embodiment 2), depending on embodiment 1), i.e. embodiment "5+2+1 " corresponds to the compounds of embodiment 1 ) further limited by the features of the embodiments 2) and 5).
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases or the like, this is intended to mean also a single compound, salt, pharmaceutical composition, disease or the like.
Any reference to a compound of formula (I) as defined in any one of embodiments 1) to 19) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example 'Handbook of Pharmaceutical Salts. Properties, Selection and Use.', P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and 'Pharmaceutical Salts and Co-crystals', Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.
The present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
Whenever the word "between" is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or 4. Unless used regarding temperatures, the term "about" (or alternatively "around") placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" (or alternatively "around") placed before a temperature Ύ" refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C. Besides, the term "room temperature" as used herein refers to a temperature of about 25°C.
The compounds of formula (I) as defined in any one of embodiments 1) to 19) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) as defined in any one of embodiments 1 ) to 19).
In a preferred embodiment of the invention, the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.
Another aspect of the invention concerns a method for the prevention or the treatment of a disease or disorder as mentioned below in a patient comprising the administration to said patient of a pharmaceutically active amount of a compound of formula (I) as defined in any one of embodiments 1 ) to 19) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
In another embodiment, the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of nasal polyposis, Still's disease (systemic onset juvenile idyiopathic arthritis) and cystic fibrosis.
In a preferred embodiment, the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of asthma, allergic asthma, eosinophilic asthma, severe asthma, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria and eczema.
In another preferred embodiment, the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
In yet another preferred embodiment, the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
In a most preferred embodiment, the compounds of formula (I) according to any one of embodiments 1 ) to 19), or pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable for the prevention and/or treatment of diseases selected from the group consisting of asthma, eosinophilic asthma, allergic rhinitis, atopic dermatitis, nasal polyposis, food allergy (notably IgE-mediated food allergy), urticaria (notably chronic urticaria), eosinophilic esophagitis, Churg Strauss Syndrome, hypereosinophilic syndrome, eosinophilic pneumonia (notably chronic eosinophilic pneumonia), DRESS syndrome, Still's disease, COPD and cystic fibrosis (and especially asthma, eosinophilic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy, chronic urticaria, eosinophilic esophagitis and Churg Strauss Syndrome).
The invention also relates to the use of a compound of formula (I) according to any one of embodiments 1) to 19) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.
The present invention also relates to pharmaceutically acceptable salts and to pharmaceutical compositions and formulations of compounds of formula (I) according to any one of embodiments 1) to 19).
A pharmaceutical composition according to the present invention contains at least one compound of formula (I) according to any one of embodiments 1) to 19) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.
Any reference to a compound of formula (I), (lSTi) or (lST2> in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The preferences indicated for the compounds of formula (I) of course apply mutatis mutandis to the compounds of formula (lSTi) and to the compounds of formula (lST2) as well as to the salts and pharmaceutically acceptable salts of the compounds of formula (I), of formula (lSTi) or of formula (lST2) - The same applies to these compounds as medicaments, to pharmaceutical compositions containing these compounds as active principles or to the uses of these compounds for the manufacture of a medicament for the treatment of the diseases according to this invention.
As mentioned earlier, compounds of formula (I) modulate as antagonists the PGD2 activation of the CRTH2 receptor. The biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays. The ability of the compounds of formula (I) to bind to the CRTH2 receptor may be measured by methods similar to those described in the literature (Arimura A. et al. , J. Pharmacol. Exp. Ther. 2001 , 298(2), 41 1 -419; and Sawyer N. et al., Br. J. Pharmacol, 2002, 137, 1 163-1 172, respectively) and by the assays described below in the experimental part.
A further aspect of the invention is a process for the preparation of compounds of formula (I). Compounds according to formula (I) of the present invention can be prepared according to the sequence of reactions outlined in the schemes below wherein R1 and R2 are as defined for formula (I). Other abbreviations used are defined in the experimental section.
In general, all chemical transformations can be performed according to well-known standard methodologies as described in the literature, or as described in the procedures below. The compounds obtained may also be converted into pharmaceutically acceptable salts thereof in a manner known per se.
The compounds of formula (I) may be prepared from the respective azaindole derivative (4) which itself may be synthesized by MW irradiation of the respective 3-amino-2-bromo- pyridine or 3-amino-2-chloro-pyridine derivative (1) with a 4-(5-chloro-pyrimidin-2-yl)amino- cyclohexanone derivative (3) in the presence of a catalyst such as Pd(Ph3P)4 in pyridine or by reaction of the respective Boc protected hydrazine derivative (6) with a 4-(5-chloro- pyrimidin-2-yl)amino-cyclohexanone derivative (3) in the presence of an acid such as sulfuric acid. The Boc protected hydrazine derivative (6) may be prepared by reaction of the respective bromo-pyridine derivative (5) with di-tert-butyl-aza-dicarboxylate in the presence of a base such as butyllithium in an aprotic solvent such as THF.
The 4-(5-chloro-pyrimidin-2-yl)amino-cyclohexanone derivative (3) may be prepared by a reductive amination of commercially available 1 ,4-dioxaspiro[4,5]decan-8-one (2) with the desired amine R2-NH2 in the presence of a reducing agent such as NaBH(OAc)3 in an aprotic solvent such as DCM, followed by reaction with 2,5-dichloropyrimidine (R3-CI) in the presence of a base such as DIEA in an aprotic solvent such as DMF, and acetal deprotection under acidic condition such as HCI in methanol. Alkylation of the azaindole derivative (4) with ethyl bromoacetate in the presence of a base such as NaH in an aprotic solvent such as DMF followed by saponification with a base such as NaOH furnished the compounds of formula (I).
1) R2-NH2/ NaBH(OAc)3/ DCM
2) R3-CI/ DIEA/ DMF
3) HCI/ MeOH
4
1) Br C02Et
NaH/ DMF
2) NaOH
(I)
Scheme 1: General synthetic route for the preparation of compounds of formula (I) (R3 represents 5-chloro-pyrimidin-2-yl)
Alternatively, compounds of formula (I) wherein R2 represents hydrogen may be prepared from the respective azaindole derivative (9) which itself may be synthesized by MW irradiation of the respective 3-amino-2-bromo-pyridine (7) with commercially available tert- butyl (4-oxocyclohexyl)carbamate (8) in the presence of a catalyst such as Pd(Ph3P)4 in pyridine.
Alkylation of the azaindole derivative (9) with ethyl bromoacetate in the presence of a base such as NaH in an aprotic solvent such as DMF followed by Boc deprotection with an acid such as HCI in dioxane gives the desired azaindole acetic acid ethylester (10). Reaction of amine (10) with 2,5-dichloropyrimidine (R3-CI) in the presence of a base such as K2C03 in an aprotic solvent such as DMA followed by saponification with a base such as NaOH furnished the compounds of formula (I).
Scheme 2: General synthetic route for the preparation of compounds of formula (I) wherein R2 represents hydrogen (R3 represents 5-chloro-pyrimidin-2-yl)
Compounds of formula (I) wherein R2 represents hydrogen may also be prepared from the respective azaindole derivative (13) which itself may be synthesized by reaction of the respective commercially available pyridine hydrazine hydrochloride derivative (11) with commercially available benzyl (4-oxocyclohexyl)carbamate (12) in the presence of an acid such as sulfuric acid. Alkylation of the azaindole derivative (13) with ethyl bromoacetate in the presence of a base such as NaH in an aprotic solvent such as DMF followed by Cbz deprotection with an acid such as HBr in acetic acid gives the desired azaindole acetic acid ethylester (14). Reaction of amine (14) with 2,5-dichloropyrimidine (R3-CI) in the presence of a base such as K2C03 in an aprotic solvent such as DMA followed by saponification with a base such as NaOH furnished the compounds of formula (I).
Scheme 3: General synthetic route for the preparation of compounds of formula (I) wherein R2 represents hydrogen (R3 represents 5-chloro-pyrimidin-2-yl) Whenever the compounds of formula (I) or an intermediate of structures 4, 9 and 13 are obtained in the form of mixtures of enantiomers, the enantiomers may be separated using methods known to the one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk- 01 (R,R) (10 μηι) column, a Daicel ChiralCel OD-H (5-10 μηι) column, or a Daicel ChiralPak IA (10 μηι) or AD-H (5 μηι) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as TEA and/or DEA) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
Experimental section:
Abbreviations (as used herein):
Ac Acetyl
aq. Aqueous
APC Allophycocyanin
Boc tert-butoxycarbonyl
BSA Bovine Serum Albumin
Cbz Benzyloxycarbonyl
d Doublet
DCM Dichloromethane Diethylamine
Λ/,/V-Diisopropylethylamine
Dimethylformamide
Dimethylacetamide
Dimethylsulfoxide
decays per minute
Ethyl acetate
Ethylene Diamine Tetraacetic Acid
Equivalent
Ethyl
Flash chromatography
Hour(s)
4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid High Performance Liquid Chromatography Human Serum Albumin
Liter(s)
Liquid Chromatography-Mass Spectroscopy
Multiplet
Acetonitrile
Methanol
Minute(s)
Methyl
Mass Spectrometry
Microwave
Normality of solution
Phosphate Buffered Saline
Polyethyleneimine
Prostaglandin D2
Phenyl
Room temperature
Second(s)
Saturated
tert-butyl
Triethylamine
Trifluoroacetic acid
Tetrahydrofuran tR Retention time
Tris Tris-(hydroxymethyl)aminomethane buffer
Chemistry
General remarks
All solvents and reagents are used as obtained from commercial sources unless otherwise indicated.
Temperatures are indicated in degrees Celsius (°C). Unless otherwise indicated, the reactions take place at room temperature (RT).
In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume relations (v/v), unless indicated otherwise.
Analytical HPLC conditions as used in the Examples below:
HPLC/MS analyses are performed on a Agilent 1 100 system, equipped with a Dionex P580 binary pump, a Dionex PDA-100 Photodiode Array Detector and a Finnigan AQA mass spectrometer.
The LC retention times are obtained using the following elution condition:
- Analytical HPLC on a Zorbax® SB-AQ column (4.6x50 mm, 3.5 μηι, Agilent); Linear gradient of water/ 0.04% TFA (A) and MeCN (B) from 5% to 95% B over 1 .5 min; flow rate 4.5 ml/min, detection at 210 nm.
Preparative HPLC/MS purifications (acidic conditions) are performed on a Gilson 333/334 binary high pressure gradient pump system with a Gilson 215 autosampler and fraction collector, a Dionex UVD340U DAD detector, a polymerlabs PL-ELS 1000 ELS detector and a Thermo MSQ Plus MS detector, using a Waters Atlantis T3 column (10 μηι, 30 χ 75 mm), with a linear gradient of water/ 0.5% formic acid (B) and MeCN (A) starting from 80/20 to 5/95 (B)/(A) over 5 min.; flow rate 75 ml/min.
Preparative HPLC/MS purifications (basic conditions) are performed on a Gilson 333/334 binary high pressure gradient pump system with a Gilson 215 autosampler and fraction collector, a Dionex UVD340U DAD detector, a polymerlabs PL-ELS 1000 ELS detector and a Thermo MSQ Plus MS detector, using a Waters XBridge C18 column (10 μηι, 30 χ 75 mm), with a linear gradient of water/ 0.5% 25% NH4OH (B) and MeCN (A) starting from 80/20 to 5/95 (B)/(A) over 5 min.; flow rate 75 ml/min.
Analytical HPLC over a chiral stationary phase are performed on a Daicel ChiralPak AD-H (4.6 X 250 mm, 5 μηι) column or a Chiralpak AY-H (4.6 X 250 mm, 5 μηι) column. Typical conditions of chiral HPLC are an isocratic mixture of 30% heptane + 0.05% DEA and 70% EtOH + 0.05% DEA, at a flow rate of 0.8 mL/min., detection at 210 nm (chiral HPLC-1 ) or an isocratic mixture of 40% heptane and 60% EtOH + 0.1 % TFA, at a flow rate of 1 .0 mL/min., detection at 210 nm (chiral HPLC-2) or an isocratic mixture of 50% heptane + 0.05% DEA and 50% EtOH + 0.05% DEA, at a flow rate of 0.8 mL/min., detection at 210 nm (chiral HPLC-3), or an isocratic mixture of 20% heptane and 80% EtOH + 0.1 % TFA, at a flow rate of 0.8 mL/min., detection at 210 nm (chiral HPLC-4).
Preparative HPLC over a chiral stationary phase are performed on a Daicel ChiralPak AD- H (20 X 250 mm, 5 μηι) column. Typical conditions of chiral HPLC are an isocratic mixture of 50% EtOH and 50% heptane, at a flow rate of 16 mL/min., detection at 210 nm (chiral HPLC-5) or an isocratic mixture of 50% EtOH + 0.05% DEA and 50% heptane, at a flow rate of 34 mL/min, detection at 210 nm (chiral HPLC-6) or an isocratic mixture of 50% EtOH + 0.1 % DEA and 50% heptane, at a flow rate of 16 mL/min, detection at 210 nm (chiral HPLC-7).
A.1 Synthesis of 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H- pyrido[3,2-fo]indol-5-yl)acetic acid derivatives
A.1.1. Synthesis of 4-((5-chloropyrimidin-2-yl)(methyl)amino)cyclohexanone
(R3 represents 5-chloro-pyrimidin-2-yl)
To a solution of commercially available 1 ,4-dioxaspiro[4.5]decan-8-one (1 eq) in DCM (20 ml/ 10 mmol), were added successively at 0°C methyl amine (8M in EtOH, 1 eq) and NaBH(OAc)3 (1 .5 eq). The reaction mixture was allowed to warm to RT and stirred for 2h. The reaction mixture was poured into a saturated solution of NaHC03, the organic layer was washed with brine, dried over MgS04 and evaporated in vacuo to give /V-methyl-1 ,4- dioxaspiro[4.5]decan-8-amine which was used for the next step without further purification. To a solution of /V-methyl-1 ,4-dioxaspiro[4,5]decan-8-amine (1 eq) in DMF (10.5 ml/ 6 mmol) were added DIEA (2 eq) and 2,5-dichloropyrimidine (1 .05 eq). The reaction mixture was stirred at 90°C overnight. After cooling to RT, isopropyl acetate was added. The mixture was washed with water and 10% aq citric acid. The organic layer was dried (MgS04) and concentrated in vacuo. The crude product was purified by FC (0 to 15% EA in heptane) to afford the desired intermediate compound as a solid. A solution of this intermediate (1 eq) in a mixture of 2N HCI (2.7 ml/ 5 mmol) and MeOH (2.7 ml/ 5 mmol) was stirred at room temperature overnight. The aqueous layer was extracted with DCM. The organic layer was dried (MgS04) and concentrated in vacuo. The crude residue was purified by FC (0 to 17% EA in heptane) to give the titled compound as a solid. LC-MS: tR = 0.78 min; [M+H]+ = 240.2
A.1.2. Synthesis of W-(5-chloropyrimidin-2-yl)-W-methyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-8-amine derivatives (method A)
(R3 represents 5-chloro-pyrimidin-2-yl) General procedure:
A solution of the respective 3-amino-2-bromo-pyridine derivative (1 eq), 4-((5- chloropyrimidin-2-yl)(methyl)amino)cyclohexanone (1 .2eq), (Ph3P)4Pd (0.05eq), and pyridine (8.17 eq) were combined in a vial. The vial was irradiated by MW at 160°C for 1 h. (PhsP^Pd (0.025eq) was added again and the reaction mixture was irradiated again by MW at 160°C for 30min. After cooling to RT, the reaction mixture was combined with water and extracted twice with DCM. The combined organic extracts were dried (MgS04), filtered and concentrated in-vacuo.
The residue was purified by prep. HPLC (basic conditions) to afford the desired product.
The following /V-(5-chloropyrimidin-2-yl)-/V-methyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-Jb]indol- 8-amine derivatives were synthetized according to the above general procedure.
Table 1
CF3 N-(5-chloropyrimidin-2-yl)-N-methyl-2-(trifluoromethyl)- 381 .99 0.94
6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-amine
A.1.3. Synthesis of W-(5-chloropyrimidin-2-yl)-W-methyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-8-amine derivatives (method B)
A.1.3.1 Synthesis of di-tert-butyl 1 -(pyridin-3-yl)hydrazine-1 ,2-dicarboxylate
General procedure:
A solution of Butyllithium solution 1 .6M in Hexane (1 .1 eq) was added dropwise at -40°C to a solution of the respective 3-bromo-pyridine derivative (1 eq) in diethylether (14.5 eq) under N2 atmosphere. The reaction mixture was stirred for 20min at -40°C and then a solution of di-tert-butyl-azodicarboxylate (1 .1 eq) in THF (18.5 eq) was added dropwise. The reaction mixture was stirred at -40°C for 30min and allowed to warm to RT over 30min. Water was added followed by DCM. The organic phase was separated and dried over MgS04, filtered and concentrated in vacuo. The residue was purified by FC (EA/n-heptane: 2/8) to afford the desired product. The following di-tert-butyl 1 -(pyridin-3-yl)hydrazine-1 ,2-dicarboxylate derivatives were synthetized according to the above general procedure
A.1.3.2 Synthesis of W-(5-chloropyrimidin-2-yl)-W-methyl-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-8-amine derivatives
(R3 represents 5-chloro-pyrimidin-2-yl)
General procedure:
A solution of the respective di-tert-butyl 1 -(pyridin-3-yl)hydrazine-1 ,2-dicarboxylate derivative (1 eq), 4-((5-chloropyrimidin-2-yl)(methyl)amino)cyclohexanone (1 eq) in aqueous 4% H2S04 (10 mL/0.04 mol) was stirred at 100°C for 2h30. After cooling to RT, the reaction mixture was combined with sat. NaHC03 and extracted with EA. The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by prep. HPLC (basic conditions) to afford the desired product
The following /V-(5-chloropyrimidin-2-yl)-/V-methyl-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-Jb]indol- 8-amine derivatives were synthetized according to the above general procedure.
A.1.3. Synthesis of 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro- 5H-pyrido[3,2-fo]indol-5-yl)acetic acid derivatives
General procedure:
To a cold (0°C) solution of the appropriate /V-(5-chloropyrimidin-2-yl)-/V-methyl-6, 7,8,9- tetrahydro-5/-/-pyrido[3,2-Jb]indol-8-amine derivative (1 eq) in dry DMF (0.2 mL/0.08 mmol), was added NaH (1 .1 eq, 60% dispersion in mineral oil). The reaction mixture was stirred at 0°C for 10 min, ethyl bromoacetate (1 .1 eq) was added and the reaction mixture was allowed to warm to RT and stirred overnight. Water (0.07 mL) and 30% aq. NaOH (0.07 ml) were added to the reaction mixture. The reaction mixture was stirred at 50°C for 2h and then 37% aq. HCI (0.07 mL) was added. The products were immediately purified by prep. HPLC (basic conditions) to provide the final compound.
Preparation of examples
The following 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2- £>]indol-5-yl)acetic acid derivatives were synthetized according to the above general procedure.
Table 2
tR [min.]
Example [M+H]+
Name LC-MS m/z
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-
1 0.64
methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- 386.01
yl)acetic acid
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-
2 0.83
fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- 390.02
yl)acetic acid
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-
3 0.66
methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol- 402.05
5-yl)acetic acid
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-
4 0.89
(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2- 440.0
b]indol-5-yl)acetic acid A.2 Synthesis of 2-(8-(5-chloropyrimidin-2-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[3,2- fo]indol-5-yl)acetic acid derivatives
A.2.1 Synthesis of fert-butyl (6,7,8,9-tetrahydro-5H-pyrido[3,2-ft]indol-8-yl)carbamate HBoc
A solution of 3-amino-2-bromopyridine (1 .0 g, 5.78 mmol, 1 .0 eq), fe/ -butyl (4- oxocyclohexyl)carbamate (1 .48 g, 6.94 mmol, 1 .2 eq), (Ph3P)4Pd (334 mg, 0.289 mmol, 0.05 eq), and pyridine (3.8 ml, 47.2 mmol, 8.17 eq) were combined in a vial. The vial was heated by MW at 160°C for 2h30. The reaction mixture was combined with a sat NaHC03 solution and extracted with EA. The organic layer was washed with water, brine, dried (MgS04), filtered and concentrated in vacuo. The residue was triturated with diethyl ether and collected by filtration to afford the titled product as a beige solid.
LC-MS: tR = 0.59 min; [M+H]+ = 288.27.
A.2.2 Synthesis of ethyl 2-(8-amino-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetate (hydrochloride salt)
To a cold (0°C) solution of te/ -butyl (6,7,8,9-tetrahydro-5H-pyrido[3,2-Jb]indol-8- yl)carbamate (403 mg, 1 .4 mmol, 1 .0eq) in dry DMF (3.8 mL) was added NaH (37 mg, 1 .54 mmol, 1 .1 eq, 60% dispersion in mineral oil). The reaction mixture was stirred at 0°C for 10 min, ethyl bromoacetate (0.16 mL, 1 .4 mmol, 1 .0eq) was added and the reaction mixture was allowed to warm to RT and stirred overnight. Water was added and the reaction mixture was extracted twice with EA. The combined organic extracts were washed with water, brine, dried (MgS04), filtered and concentrated in vacuo. The residue was purified by prep-HPLC (acidic conditions) to give the desired product. LC-MS: tR = 0.67 min; [M+H]+ = 373.96.
To ethyl 2-(8-((fe/?-butoxycarbonyl)amino)-6 ,7,8,9-tetrahydro-5/-/-pyrido[3,2-Jb]indol-5- yl)acetate (23 mg, 0.06 mmol, 1 .0 eq) was added HCI in dioxane (4M, 0.21 ml, 0.85 mmol, 14 eq) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to give the titled product which was used for the next step without further purification.
LC-MS: tR = 0.37 min; [M+H]+ = 273.91
A.2.3 Synthesis of 2-(8-(5-chloropyrimidin-2-ylamino)-6,7,8,9-tetrahydro-5H- pyrido[3,2-fo]indol-5- l acetic acid derivatives
(R3 represents 5-chloro-pyrimidin-2-yl)
General procedure:
A mixture of ethyl 2-(8-amino-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-Jb]indol-5-yl)acetate (hydrochloride salt) (0.06 mmol), 2,5-dichloropyrimidine (0.06 mmol), and K2C03 (0.25 mmol) in DMA (0.4 mL) was stirred at 80°C for 12h. After cooling to RT, water (0.06 mL) and 30% aq NaOH (0.06 mL) were added to the reaction mixture. The reaction mixture was stirred at 50°C for 2h and then 37% aq HCI (0.06 mL) was added. The products were immediately purified by prep. HPLC (basic conditions) to provide the final compounds as a white solid.
Preparation of examples
The following 2-(8-(5-chloropyrimidin-2-ylamino)-6,7,8,9-tetrahydro-5/-/-pyrido[3,2-Jb]indol-5- yl)acetic acid derivatives were synthetized according to the above general procedure.
Table 3
tR [min.]
Example [M+H]+
Name LC-MS m/z
5 2-(8-((5-chloropyrimidin-2-yl)amino)-6, 7,8,9- 0.56
358.1
tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid A.3 Synthesis of (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro- 5H-pyrido[3,2-b]indol-5-yl)acetic acid
A.3.1 Synthesis of fert-butyl methyl(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8- yl)carbamate
In a vial, 3-amino-2-bromopyridine (2.0 g, 1 1 .6 mmol, 1 .0 eq), 4-(N-Boc-N- methylamino)cyclohexanone (3.15 g, 13.9 mmol, 1 .2 eq), and (Ph3P)4Pd (668 mg, 0.58 mmol, 0.05 eq) were dissolved in pyridine (7.6 ml). The vial was heated by MW irradiation at 160°C for 60 min. The reaction mixture was poured into water (9.5 mL) and the resulting solid was collected by filtration, dried, triturated in diethyl ether and collected again by filtration to afford the titled compound.
LC-MS: tR = 0.63 min; [M+H]+ = 302.15.
A.3.2 Synthesis of (S)-ethyl 2-(8-((fert-butoxycarbonyl)(methyl)amino)-6,7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetate and (R)-ethyl 2-(8-((iert- butoxycarbonyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-£)]indol-5-yl)acetate
To a cold (0°C) solution of te/ -butyl methyl(6,7,8,9-tetrahydro-5H-pyrido[3,2-Jb]indol-8- yl)carbamate (1 .37 g, 4.56 mmol) in dry DMF (12.5 mL), was added NaH (120 mg, 5.02 mmol, 60% dispersion in mineral oil). The reaction mixture was stirred at 0°C for 10 min, ethyl bromoacetate (0.52 mL, 4.56 mmol) was added and the reaction mixture was allowed to warm to RT and stirred overnight. Water was added and the resulting precipitate was collected by filtration and washed with water. The crude solid was purified by FC (8% MeOH in DCM) followed by trituration with diethyl ether to provide the desired product as a race mate.
LC-MS: tR: 0.7 min./ [M+H]+: 388.50
The two enantiomers of the obtained product were separated by preparative chiral HPLC (chiral HPLC-5):
(R)-ethyl 2-(8-((te/ -butoxycarbonyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2- £>]indol-5-yl)acetate
(487 mg, 28%): HPLC (chiral HPLC-1 ): tR: 6.03 min;
(S)-ethyl 2-(8-((te/ -butoxycarbonyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2- £>]indol-5-yl)acetate
(491 mg, 28%): HPLC (chiral HPLC-1): tR: 7.36 min.
A.3.3. Synthesis of (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid (example 6)
To (S)-ethyl 2-(8-((te/ -butoxycarbonyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2- Jb]indol-5-yl)acetate (100 mg, 0.258 mmol) was added 4N HCI in dioxane (0.895 mL). The reaction mixture was stirred at RT for 1 h and concentrated to give the desired product as a hydrochloride salt which was used in the next step without further purification.
LC-MS: tR: 0.38 min./ [M+H]+: 288.25.
To a solution of this intermediate (93 mg, 0.26 mmol) in DMA (1 .8 mL) were added 2,5- dichloropyrimidine (38.5 mg, 0.26 mmol) and K2C03 (143 mg, 1 .03 mmol). The reaction mixture was stirred at 80°C for 20h. After cooling to RT, water (0.26 mL) and 30% aq NaOH (0.26 mL) were added and the reaction mixture was stirred at 50°C for 2h. Then 37% aq HCI (0.26 mL) was added, and the resulting precipitate was filtered off and purified by prep-HPLC (basic conditions) to give the titled compound as a white solid.
LC-MS: tR: 0.61 min./ [M+H]+: 372.18.
HPLC (chiral HPLC-2): tR: 7.87 min. A.4 Synthesis of (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6, 7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid
A.4.1 Synthesis of (S)-ethyl 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro- 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetate and (R)-ethyl 2-(8-((5- chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetate
NaH 95% (56.1 mg, 2.22 mmol, 1 .2 eq) was added carrefully to a cold solution (0°C) of N- (5-chloropyrimidin-2-yl)-2-fluoro-N-methyl-6 ,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-amine (614 mg, 1 .85 mmol, 1 eq) in DMF (6.36 mL). The reaction mixture was stirred for 20 min. Ethyl bromoacetate (0.233 mL, 2.04 mmol, 1 .1 eq) was added slowly and the reaction mixture was allowed to warm at RT and stirred for 2h. The reaction mixture was dissolved in EA, and washed with a saturated solution of NaHC03. The organic extract was dried over MgS04, filtered and concentrated in vacuo. The residue was purified by FC (n- heptane to n-heptane/EA: 7/3) to give the desired product as a racemate.
LC-MS: tR: 0.96 min./ [M+H]+: 418.01
The two enantiomers of the obtained product were separated by preparative chiral HPLC (chiral HPLC-6):
(S)-ethyl 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetate
(271 mg, 35%): HPLC (chiral HPLC-3): tR: 6.22 min;
(R)-ethyl 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetate
(273 mg, 35%): HPLC (chiral HPLC-3): tR: 7.66 min.
A.4.2 Synthesis of (S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid (example 7)
To a solution of (S)-ethyl 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6, 7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetate (271 mg, 0.649 mmol, 1 eq) in THF (10 mL) was added NaOH 1 N (10 mL, 10 mmol, 15.42 eq) at RT. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to remove only THF. It was then acidified with HCI cone, to pH~5-6 and stirred at RT. The suspension was extracted with EtOAc (4x). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo to give the title compound as a beige solid (255 mg, 100%).
LC-MS: tR: 0.82 min./ [M+H]+: 390.12
HPLC (chiral HPLC-2): tR: 4.96 min.
A.5 Synthesis of (S)-2-(8-((5-chloropyrimidin-2-yl)amino)-2-fluoro-6,7,8,9-tetrahydro- 5H-pyrido[3,2-fo]indol-5-yl)acetic acid
A.5.1 Synthesis of benzyl (2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8- yl)carbamate
A solution of 2-fluoro-5-hydrazinylpyridine hydrochloride (200 mg, 1 eq), benzyl (4- oxocyclohexyl)carbamate (296 mg, 1 eq) in aqueous 4% H2S04 (3.3 mL) was stirred at 80°C for 16h. After cooling to RT, the reaction mixture was combined with sat. NaHC03 and extracted with EA. The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo to afford the desired product (305 mg, 77%) which was used for the next step without further purification.
LC-MS: tR: 0.82 min./ [M+H]+: 340.13. A.5.2 Synthesis of (S)-ethyl-2-(8-(((benzyloxy)carbonyl)amino)-2-fluoro-6, 7,8,9- tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetate and (R)-ethyl-2-(8-
(((benzyloxy)carbonyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-£)]indol-5- yl)acetate
NaH 95% (20.8 mg, 2.22 mmol, 1 .2 eq) was added carrefully to a cold solution (0°C) of benzyl (2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-Jb]indol-8-yl)carbamate (295 mg, 1 .85 mmol, 1 eq) in DMF (6.36 ml_). The reaction mixture was stirred for 10 min. Ethyl bromoacetate (0.086 ml_, 1 .1 eq) was added slowly and the reaction mixture was allowed to warm at RT and stirred for 4h30. Additional NaH 95% was added (3.5 mg, 0.2 eq) followed by ethyl bromoacetate (0.016 ml_, 0.2 eq). The reaction was stirred at RT for 16h. The reaction mixture was then dissolved in EA, and washed with a saturated solution of NaHC03. The organic extract was dried over MgS04, filtered and concentrated in vacuo. The residue was purified by FC (n-heptane to n-heptane/EA: 1 /1 ) to give the desired product as a racemate (150mg, 50%).
LC-MS: tR: 0.9 min./ [M+H]+: 426.15
The two enantiomers of the obtained product were separated by preparative chiral HPLC (chiral HPLC-7):
(R)-ethyl-2-(8-(((benzyloxy)carbonyl)amino)2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- £>]indol-5-yl)acetate
(67 mg, 23%): HPLC (chiral HPLC-3): tR: 5.96 min;
(S)-ethyl-2-(8-(((benzyloxy)carbonyl)amino)2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- £>]indol-5-yl)acetate
(86 mg, 29%): HPLC (chiral HPLC-3): tR: 7.27 min.
A.5.3 Synthesis of (S)-ethyl-2-(8-amino-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- fo]indol-5-yl)acetate (hydrobromide salt)
To a solution of (S)-ethyl-2-(8-(((benzyloxy)carbonyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5/-/- pyrido[3,2-Jb]indol-5-yl)acetate (42 mg, 1 eq) in acetic acid (1 mL) was added HBr 33% in acetic acid (0.22 mL). The reaction mixture was stirred at RT for 1 h and concentrated in vacuo to give the title product (94 mg, 100%) which was used for the next step without further purification
LC-MS: tR: 0.55 min./ [M+H]+: 292.12
A.5.4 Synthesis of (S)-2-(8-((5-chloropyrimidin-2-yl)amino)-2-fluoro-6, 7,8,9- tetrahydro-5H-pyrido[3,2-fo]indol-5-yl)acetic acid (example 8)
To a solution of (S)-ethyl-2-(8-amino-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2-Jb]indol-5- yl)acetate (hydrobromide salt) (48 mg, 1 eq) in DMA (1 mL) were added successively 2,5- dichloropyrimidine (15.6 mg, 1 .4 eq) and anhydrous K2C03 (41 .5 mg, 4 eq). The reaction mixture was stirred at 80°C for 16h. After cooling to RT, the reaction was poured into water and extracted with EA. The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (acidic conditions) to give the intermediate ethyl ester (9 mg, 30%).
LC-MS: tR: 0.88 min./ [M+H]+: 404.05
To a solution of the ethyl ester intermediate (9 mg, 1 eq) in THF (0.5 mL) was added 1 N NaOH (0.5 mL). The reaction mixture was stirred at RT for 1 h, acidified until pH 1 -2 with 1 N HCI and extracted with EA. The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo to give the title compound as a beige solid (6 mg ,24%). LC-MS: tR: 0.75 min./ [M+H]+: 376.18
HPLC (chiral HPLC-4): tR: 6.6 min.
A.6 Synthesis of (S)-2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-3,4-dihydro-1 H- carbazol-9(2H)-yl)acetic acid (reference example 1 )
A.6.1 Synthesis of (S)-methyl 2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-1 , 2,3,4- tetrahydro-9H-carbazol-9-yl)acetate and (R)-methyl 2-(3-((5-chloropyrimidin-2- yl)(methyl)amino)-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)acetate
To a solution of 2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-3,4-dihydro-1 H-carbazol- 9(2H)-yl)acetic acid (described as example 53 in WO 2011/1 17798) (100 mg, 0.27 mmol) in MeOH (1 ml), was added concentrated H2S04 (0.2 eq). The reaction mixture was stirred at reflux for 2h. The reaction mixture was concentrated in vacuo and the residue was combined with a sat NaHC03 solution and extracted with EA. The combined organic extracts were washed with brine, dried over MgS04 and evaporated in vacuo to provide the desired product as a racemate (86 mg, 83%).
LC-MS: tR: 1 .01 min./ [M+H]+: 385.10
The two enantiomers of the obtained product were separated by preparative chiral HPLC (chiral HPLC-5):
(S)-methyl 2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-1 ,2,3,4-tetrahydro-9H-carbazol-9- yl)acetate
(22 mg, 21 %): HPLC (chiral HPLC-1): tR: 7.21 min; and
(R)-methyl 2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-1 ,2,3,4-tetrahydro-9H-carbazol-9- yl)acetate
(21 mg, 20%): HPLC (chiral HPLC-1): tR: 9.06 min.
A.6.2 Synthesis of (S)-2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-3,4-dihydro-1 H- carbazol-9(2H)-yl)acetic acid (reference example 1 )
To a solution of (S)-methyl 2-(3-((5-chloropyrimidin-2-yl)(methyl)amino)-1 ,2,3,4-tetrahydro- 9H-carbazol-9-yl)acetate (22 mg) in THF (1 ml) was added 5N NaOH (10 eq). The reaction mixture was stirred at RT for 2h, acidified with concentrated HCI and stirred at RT. The resulting precipitate was filtered and dried to give the title compound as a white solid.
LC-MS: tR: 0.93 min./ [M+H]+: 371 .13.
HPLC (chiral HPLC-2): tR: 4.59 min.
Biological assays:
Preparation of hCRTH2 receptor membranes and radioligand displacement assay:
First, recombinant HEK293-hCRTH2 cells were detached from culture plates into 5 ml buffer A/plate (Buffer A: 5 mM Tris, 1 mM MgCI2-6H20 pH=7.4) using a rubber policeman. Cells were then transferred into centrifugation tubes and centrifuged for 5min at 400 g. The cell pellet was resuspended in the same buffer and tubes were frozen at -80°C. Cells were thawed and membrane fragments were generated by homogenization using a polytron homogenizer (30 seconds). The membrane fragments were then centrifuged at 3000 g for 20 minutes and resuspended in buffer C (Buffer C: 75 mM Tris , 25 mM MgCI2, 250 mM Saccharose pH 7.4). Aliquots of membrane fragements were stored at -20°C.
Binding assay was performed in a final assay volume of 250 μΙ. First, 25 μΙ of test compound, previously diluted in Binding-Buffer (Binding-Buffer: 50 mM Tris-Base, 100 mM NaCI, 1 mM EDTA, 0.1 % BSA (protease free), 0.01 % NaN3, 10mM MnCI2 pH 7.0) was placed into each well. After addition of 75 μΙ Binding-Buffer, 50 μΙ of the radioligand 3H- PGD2 (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well. Binding assay was started by addition of 100 μΙ CRTH2 membrane fragments, reaching a final concentration of 20μg/well. For non-specific binding, PGD2 was added to the reaction mixture to 10 mM final concentration. This assay mix was incubated for 90 minutes at room temperature and then filtered through a GF/C filter 96-well plate which was pre- soaked for 3 hours in 0.5% polyethyleneimine (PEI). The filter-wells were washed three times with ice cold Binding-Buffer. Then, 40 μΙ of Microscint-40 (Packard) was added to each well and the retained radioactivity quantified in a Topcount (Packard). Antagonistic activities of exemplified compounds are displayed in Table 4.
Radioligand Displacement Assay-Human Serum Albumin (HSA):
Radioligand displacement assay in presence of human serum albumin (HSA) was performed as described above, with following modifications. Binding-Buffer-HSA: Binding- buffer + 0.5% Sigma Albumin from Human serum A1887 (instead of 0.1 % BSA). A volume of 25 μΙ test compound, previously diluted in Binding-Buffer-HSA was placed into each well. After addition of 75 μΙ Binding-Buffer-HSA, 50 μΙ of 3H-PGD2 (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well. Remaining protocol was identical as described above.
Antagonistic activities of exemplified compounds are displayed in Table 5.
IC50
Example Name
[nM]
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6,7,8,9-
1 3.9 tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid 2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6, 7,8,9-
2 2.3 tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6, 7,8,9-
3 13 tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-
4 16 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid
2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro-5H-
5 22 pyrido[3,2-b]indol-5-yl)acetic acid
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-
6 2.1 tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-
7 5.0 tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid
(S)-2-(8-((5-chloropyrimidin-2-yl)amino)-2-fluoro-6, 7,8,9-
8 22 tetrahydro-5/-/-pyrido[3,2-Jb]indol-5-yl)acetic acid
Eosinophil Shape Change assay with human Plasma
After obtaining informed consent, blood samples were drawn by venipuncture according to the protocol approved by the ethics committee of Basel, Switzerland. Polymorphonuclear leukocytes (containing eosinophils, basophils and neutrophils) were isolated using the Polymorphprep™ method (Axis-Shield). In brief, anticoagulated whole blood was layered onto a Polymorphprep gradient (density 1 .1 13 g/ml) and centrifuged at 500 g for 30 min. The polymorphonuclear cell fraction was harvested and depleted for erythrocytes by hypotonic saline lysis. The polymorphonuclear cells were resuspended in assay buffer (1 x PBS with Ca2+/Mg2+ supplemented with 0.1 % BSA, 10 mM HEPES, and 10 mM Glucose, pH 7.4) at 5x 106 cells/ml and stained with anti-CD49d-APC ((APC=Allophycocyanin) for 1 hour at RT. Test compounds, at various concentrations, were preincubated 10min in human plasma (anticoagulated with a thrombin inhibitor). Then, human plasma was added to the polymorphonuclear cells to 50% of final assay volume with polymorphonuclear cells at 4x106 cells/ml. After incubation for 10 minutes at 37°C, the polymorphonuclear cells were activated for 5 min at 37°C by addition of PGD2 at 100 nM final concentration. Activation was stopped by addition of 0.5 ml paraformaldehyde (1 %).
Immediately after fixation with paraformaldehyde, the samples were analyzed by FACSCanto flow cytometer (BD Biosciences) and target cells were identified by their forward-scatter (FSC) and side-scatter (SSC) characteristics. Eosinophils were identified by the anti-CD49d-APC signal and their characteristic side-scatter (SSC) profile. Shape change responses, indicative of eosinophil activation, were quantified as the percent of cells with an increased forward-scatter. Antagonistic activities of exemplified compounds are displayed in Table 6.
Intracellular calcium mobilization assay (FLIPR):
Cells (HEK-293), stably expressing the hCRTH2 receptor under the control of the cytomegalovirus promotor from a single insertion of the expression vector pcDNA5 (Invitrogen), are grown to confluency in DMEM (low glucose, Gibco) medium supplemented with 10% fetal calf serum (Bioconcept, Switzerland) under standard mammalian cell culture conditions (37°C in a humidified atmosphere of 5% C02). Cells are detached from culture dishes using a dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, and collected by centrifugation at 200 g at rt for 5 min in assay buffer (equal parts of Hank's BSS (HBSS, Bioconcept) and DMEM (low glucose, without phenol red, Gibco)). After incubation for 45 min (37°C and 5% C02) in the presence of 1 μΜ Fluo-4 and 0.04% Pluronic F-127 (both Molecular Probes), and 20 mM HEPES (Gibco) in assay buffer, the cells are washed with and resuspended in assay buffer, then seeded onto 384-well FLIPR assay plates (Greiner) at 50,000 cells in 66 μΙ per well, and sedimented by centrifugation.
Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in assay buffer to concentrations required for inhibition dose response curves. Prostaglandin D2 (Biomol, Plymouth Meeting, PA) is used as an agonist.
A FLIPR Tetra instrument (Molecular Devices) is operated according to the manufacturer's standard instructions, adding 4 μΙ of test compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. 10 μΙ of 80 nM prostaglandin D2 (Biomol, Plymouth Meeting, PA) in assay buffer, supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%, Sigma), is then added to obtain a final concentration of 10 nM and 0.1 %, respectively. Changes in fluorescence are monitored before and after the addition of test compounds at λβχ=488 nm and λβΓτι=540 nm. Emission peak values above base level after prostaglandin D2 addition are exported after base line subtraction. Values are normalized to high-level control (no test compound added) after subtraction of base line value (no prostaglandin D2 added). The program XLIfit 3.0 (IDBS) is used to fit the data to a single site dose response curve of the equation (A+((B-A)/(1 +((C/x)AD)))) and to calculate the IC50 values.
In vitro cytotoxicity in primary cultured rat hepatocytes
1 . Methods
1 .1 Isolation and culture of rat hepatocytes
Adult male Wistar rats were narcotized with sodium pentobarbital and hepatocytes were isolated according to a standard procedure, i.e. by in situ perfusion of the liver with a collagenase solution. The viability of the purified hepatocytes, checked by the trypan blue dye exclusion method was greater than 85%. The isolated hepatocytes were resuspended in standard Williams Medium E, without phenol red, supplemented (WME supp.) with transferrin (100 μg/ml), triiodothyronine (10 μg/ml), gentamicin (50 μg/ml), hydrocortison hemisuccinate (13.36 μg/ml), glucagon (5 μg/ml), HEPES (10 mM), inosin (10 μg/ml), insulin (10 μg/ml), streptomycin (100 μg/ml) and penicillin (100 U/ml) and 10% fetal bovine serum (FBS). The cells were plated in collagen-coated 24-well plates at an initial density of 2x105 cells/well. After 4 h for attachment to the culture-plates, the medium was aspirated and replaced by fresh WME supp. without FBS containing the test compounds and incubated for 24 h at 37°C in a 95% 02 and 5% C02 atmosphere. For each experiment, i.e., with each batch of hepatocytes, treatments with the test compounds were done in quadriplicate. Quadriplicate controls (treatment with the vehicle only) were also present on each culture plate.
1 .2 In vitro exposure to the test compounds
Stock solutions of the test compounds were prepared in DMSO a few hours before treatment start. Appropriate dilutions of these stock solutions were added to the culture media just prior to the treatment in order to give final concentrations of 0, 3, 10, 30, 100 and 300 μΜ. The final concentration of the vehicle DMSO was 1 % (v/v).
1 .3 Viability of the cell cultures
1 .3.1 Monitoring of monolayer morphology
The morphology of the hepatocyte monolayers was monitored by light microscopy after 24 hours of exposure to the test compounds. Treatment related effects are described according to the following grading:
0 No morphological alterations observed upon treatment when compared to the control cultures
1 -3 Treatment resulting in any morphological changes, e.g. intracellular granulation, vacuolization or cell death. Depending on the severity, these changes were regarded as slight (1), moderate (2) or strong (3).
K Treatment resulting in 100% dead cells and/or the complete detachment of the monolayer yielding a clear cell-free dish.
1 .3.2 Leakage of lactate dehydrogenase
After 24 h treatment of the hepatocyte cultures, aliquots of culture medium were carefully collected and used for the analysis of lactate dehydrogenase (LDH) activity by spectrophotometry using the LDH cytotoxicity detection kit from Clontech (cat No. 630117, Mountain View, CA, USA). For each experiment, additional cultures were used for the determination of total intracellular LDH activity at treatment start. For this purpose, 4 wells of cell culture per experiment were washed with cold saline before treatment start, sonicated in fresh medium and the homogenate was analyzed for total LDH activity. Enzyme activities in the culture media were assessed and expressed as percentage of the total activity present in the cultured hepatocytes at the beginning of the treatments.
2. Data analysis
The lowest cytotoxic concentration (LCC) and the no effect concentration (NoEC) are given for each compound, based on cell morphology and LDH leakage after 24 h treatment. LCC is defined as the lowest concentration of the test compound leading to a clear effect on the cultured rat hepatocytes (morphology grading > 2 or > 2-fold increase in LDH leakage). A LCC value of >300 μΜ indicates the absence of effect on both endpoints at the highest test concentration of 300 μΜ. Compounds that exhibited only a slight cytotoxicity (morphology grading 1 or < 2-fold increase in LDH leakage) at the highest test concentration were marked as "300s". NoEC is defined as the highest test concentration of the compound which was without an effect on the cultured rat hepatocytes (morphology and LDH leakage).
3. Results
Table 7. LCC values of exam le compounds
in-vivo liver toxicity:
Liver toxicity of a compound of formula (I) can be analyzed by oral treatment in rats and a non-rodent species of up to 4 weeks using three different doses of the compound. Reversibility of possible toxicity can be investigated in a subsequent treatment free period (recovery period). Dose levels are chosen based on dose range finding studies in the respective species. The high dose is expected to identify organ toxicity close at the maximum tolerated dose. The mid and low dose is chosen based on estimated therapeutic human exposures. Exposure of the compound is measured at each dose level.
At end of treatment and end of recovery liver biomarkers (such as for example liver enzymes, protein, triglycerides or cholesterol) are measured in the blood. In addition, Hematoxi!in-Eosin stained liver slices is examined microscopically to directly assess possible organ damage. Specialized stainings of liver slices might be required to further characterize possible liver findings.

Claims

Claims:
1 . A compound of formula (I):
(I)
wherein
R1 represents hydrogen, (C^alkyl, (C^fluoroalkyl, (C^alkoxy, or halogen; and
R2 represents hydrogen or methyl;
or a salt of such a compound .
2. A compound according to claim 1 , wherein
R1 represents hydrogen, methyl, trifluoromethyl, methoxy, or fluoro;
or a salt of such a compound .
3. A compound according to claim 1 , wherein
R1 represents hydrogen, (C^alkyl, or (C^alkoxy;
or a salt of such a compound .
4. A compound according to claim 1 , wherein
R1 represents hydrogen, methyl, or methoxy;
or a salt of such a compound .
5. A compound according to claim 1 , wherein
R1 represents fluoro;
or a salt of such a compound .
6. A compound according to any one of claims 1 to 5, wherein
R2 represents methyl;
or a salt of such a compound .
7. A compound of formula (I) according to any one of claims 1 to 6, wherein the absolute configuration of the stereogenic center is as depicted in formula (ISti)
or a salt of such a compound.
8. A compound according to claim 1 selected from the group consisting of:
2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid;
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid;
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid; and
2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetic acid;
or a salt of such a compound.
9. A compound according to claim 1 selected from the group consisting of:
(S)-2-(8-((5-chloropyrimidin-2-yl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5-yl)acetic acid;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-5- yl)acetic acid;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-fluoro-6,7,8,9-tetrahydro-5H-pyrido[3,2- b]indol-5-yl)acetic acid;
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-methoxy-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetic acid; and
(S)-2-(8-((5-chloropyrimidin-2-yl)(methyl)amino)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- pyrido[3,2-b]indol-5-yl)acetic acid;
or a salt of such a compound.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
1 1 . A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a medicament.
12. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of a disease selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
13. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of a disease selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
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